Human CCR7^lowCD45RA^high effector memory CD8⁺ T cells (terminally differentiated T_EMRA) are reportedly a functionally compromised population with characteristics of cellular senescence when examined ex vivo. Although their frequencies are increased in elderly subjects in association with declined immune competence, however, it remains unclear whether their impaired functions can be reversed so that they contribute to immune responses in vivo. Here, I show that, in contrast to TCR stimulation, stimulation of T_EMRA with IL-15 induced a unique transcriptional signature, promoted IFN-γ production and cell cycle entry, and reduced chemotaxis toward sphingosine-1-phosphate (S1P). T_EMRA preferentially accumulated in non-lymphoid tissues when transferred into IL-15-treated NOD.SCID.γc-deficient mice compared with non-treated mice. This accumulation was impaired by S1P receptor 1 over-expression. These results suggest that T_EMRA act as functional effector T cells in non-lymphoid tissues when IL-15 is abundant and that IL-15 treatment may be beneficial in enhancing vaccine efficacy in elderly people.